9 alpha-fluoro-5 alpha, 22 alpha-spirostanes



United States Patent 2,858,308 9oc-FLUOR0-5a,22a-SPIROSTANES 5 6 Claims.(Cl. 260-43955) This application is a continuation-in-part of our U. S.application, Serial No. 576,259, filed April, 5, 1956.

This invention relates to the synthesis of, valuable steroids and hasfor its object the provision of (I) an advantageous process of preparingcortisone, and (II) certain steroids of the spirostane series useful asintermediates in the preparation of cortisone.

The process of this invention essentially comprises: (a) interactingl15,l2,8-epoxy-Sa,22a-spirostane-3fi-ol or a 3- ester thereof withhydrogen fluoride to form 9u-fluoro- 5a,22a-spirostane-3,8,IZB-diol or a3-ester thereof; (b) oxidizing the latter to the corresponding9a-fluoro-5a,22aspirostane-BB-ol-lZ-one 3-ester; (c) dehydrofluorinatingthe resultant compound to 9(1l)-dehydrohecogenin; and (d) converting thedehydrohecogenin, by methods known in the art, to cortisone.

The new steroid intermediates of this invention are those of the generalformula:

R! RI! F Q /5\/ R O I wherein R is hydrogen or acyl (particularly anacyl radical of a hydrocarbon carboxylic acid having less than tencarbon atoms), R is hydrogen, R is ,B-hydroxy or fiacyloxy (particularlyan acyloxy radical of a hydrocarbon carboxylic acid having less than tencarbon atoms), and together R and R is keto.

To prepare the intermediates of this invention, 11,13,125-epoXy-Sa,22a-spirostane-3B-ol or a 3-ester thereof (particularly anester With a hydrocarbon carboxylic acid having less than ten carbonatoms as exemplified by the lower fatty acids) is interacted withhydrogen fluoride, preferably in an inert organic solvent. This reactionyields a mixture of products, as more fully detailed in saidapplication, Serial No. 576,259, the major product being the desired9a-fluoro-5a,22a-spirostane-3fi,12fi-diol or 3-ester thereof (if anesteiified starting material is employed).

The 9a-fluoro derivative can then be acylated by treatment with an acylhalide or acid anhydride (particularly a chloride or anhydride of ahydrocarbon carboxylic acid having less than ten carbon atoms, asexemplified by acetic anhydride) in an organic solvent (particularly anorganic base, such as pyridine), to yield the 3,12-diester.

The 9a-fluoro-5u,22a-spirostane-3,6,IZB-diol 3-ester can then beoxidized to the corresponding 12-keto derivative in the usual. manner,as by treatment With chromic acid. The resultant9ot-fluoro-5u,22a-spirostane-3B-ol-12-one 3- latterconverted to estercan then be dehydrofiuorinated to 9(l1)-dehydro- .hecogenin bytreatmentwith a base such as an alkali (e. g.,

potassium hydroxide), preferably in an organic medium, such as methanol.

The resultant 9(11)-dehydrohecogenin is a known compound which, afteracylation (e. g., acetylation), can be hydrogenated torockogenin acetateand the latter oxidized to hecogenin acetate by the method disclosed byWagner et al., J. Amer. Chem. Soc., 73, 2494 (1951), andthe cortisone bymethods known in the art..(see Progress in the Chemistry of OrganicNatural Products, volume 10, page 351, Springer, Vienna, 1953).

The following examples are illustrative of the invention (alltemperatures being in Centigrade):

Into a solutionof 2 g. of 1 1 6,l2B-epoxy-5a,22a-spirostaneQB-ol.3-acetate in 76. ml; of chloroform and 4 ml. of absolute alcohol ispassed with stirring at 0 a stream of hydrogen fluoride. After 10minutes, two layers form, and the addition of hydrogen fluoride, isterminated. After minutes at 0, the reaction mixture. is neutralizedwith a suspension of sodium bicarbonate in water and the layersseparated. The chloroform is washed with Water, dried over sodiumsulfate and evaporated to dryness in vacuo. The crystalline residue uponone crystallization from chloroform-alcohol furnishes pure9ocfll101O-50t,22aspirostane-3B,12;3-diol 3-acetate, having thefollowing properties: M. P. about 25l-252; [cal 70 (c, 0.96 inchloroform);

ANuiol max.

Analysis.-Calc. for C H O F (534.66): C, 69.64; H, 8.86. Found: C,69.76; H, 8.61.

By substituting 11B,12/3-epoxy-5a,22a-spirostane3/3-ol for the 3-acetatein the procedure of Example 1, 9m-fluoro- 5a,22a-spirostane-3;8,l28-diol is obtained. 7

To a solution of 1.1 g. of 9a-fluoro-5a,22a-spirostane- 3,8,12,8-diol3-acetate in ml. of acetone is added with stirring 1.3 ml. of a solutionmade up by dissolving 200 mg. of chromic acid and 320 mg. ofconcentrated sulfuric acid in 1 ml. of Water. After the addition of 1ml. of alcohol, water is added and the acetone removed in vacuo. Theresidual suspension is extracted with chloroform, the chloroformsolution Washed with water, dilute bicarbonate and again with Water,dried over sodium sulfate and evaporated to dryness in vacuo. Theresulting 9oc-fl1l01O-5a,- 22a-spirostane-3B-ol-12-one B-acetate, afterrecrystallization from 95% alcohol, has the following properties: M. P.about 256257; [al 24 (c, 1.16 in CHC1 A nalysis.Calc. for C29H43O5F(490.63): c, 70.99; H, 8.83. Found: c, 71.27;,11, 8.63.

EXAMPLE 4 9(11)-dehydr0hec0genin A solution of 20 mg. of9a-fluoro-5a,22a-spirostane-3,8- ol-12-one 3-acetate in 2 ml. of 2 /2KOH in methanol is refluxed for one hour, the resulting mixture dilutedwith water and the methanol removed in vacuo. The resulting suspensionis extracted with chloroform, the chloroform extract washed with water,dried over sodium sulfate and evaporated to dryness in vacuo.Recrystallization from 95 alcohol gives the known 9(11)-dehydrohecogeninof the following properties: M. P. about 223- 225; [M 10 (1.01 in CHC1 A3 2.38 m (e=12,000)

Acetylation with pyridine and acetic anhydride, as described in Example1, gives 9(11)adehydrohecogenin acetate, M. P. 220221, identical in itsinfrared spectrum with an authentic sample.

The invention may be otherwise variously embodied within the scope ofthe appended claims.

max.

4 We claim: 1. A compound of the general formula wherein R is selectedfrom the group consisting of hydrogen and the acyl radical of a lowerfatty acid, R is hydrogen, R" is selected from the group consisting of,B-hydroxy and the fi-acyloxy radical of a lower fatty acid, andtogether R and R" is keto.

2. An ester of 9u-fluoro-5a,22a-spirostane-3B,12fi-dio1 and a lowerfatty acid. v

3. 9a-fluoro-5u,22a-spirostane-3,8,IZB-diol 3-acetatey 5. An ester of9a-fluoro-5a,22aspirostane-3fi-ol-12- one and a lower fatty acid.

No references cited.

1. A COMPOUND OF THE GENERAL FORMULA